We pioneered the concept of signal transduction therapy with CAI and are now completing our phase I study of CAI in combination with paclitaxel and our phase II study of single agent CAI in ovarian cancer. We continue to find activity with limited toxicity. The phase II study demonstrates a 33% rate of response and disease stabilization in women with measurable recurrent ovarian cancer. Toxicity has been mild and the pharmacokinetic monitoring suggests only a small number of patients are not optimally treated at a dose of 250 mg/m2 per day administered in the morning, fasting. Our phase I study of daily CAI with 3 weekly paclitaxel is completing accrual at the highest dose level without dose limiting toxicity, but with consistent findings of benefit, especially in ovarian cancer, cervix cancer, and melanoma. Continued efforts are underway to profile the signaling pathways regulated by CAI (see Signaling Pathways as Molecular Targets in Angiogenesis). Collaboration continues investigating the application of CAI for ophthalmologic use. Excellent scleral permeability has been found in ex vivo models and it has been shown to be problematic when used in implant form due to hygroscopicity altering release over time. No direct ocular toxicity has been identified to date in the rabbit models with implants and the screening observations in the patients on the phase II trial have yielded no drug-related ophthalmologic toxicity. We are expanding our approach to signal transduction therapy to apply microproteomics for the analysis of signal pathway modulation in situ in the cancer. Microdissection and proteomic tissue lysate array profiling will be used to assess the clinical effects in the tumor of the activity of STI-571 and ZD1839 administered to women with recurrent ovarian cancer. Sentinel tumor lesions are biopsied prior to initiation of therapy and then at 1 month. Stroma and tumor will be microdissected and subjected to array to analyze the initial and downstream activity of regulation of these pathways. This approach permits the opportunity to evaluate in situ the effects of circulating drug on the putative tumor and stromal targets. Both clinical trials are now accruing patients and proteomic analysis is to begin.